miR-1303 regulates BBB permeability and promotes CNS lesions following CA16 infections by directly targeting MMP9.
miR-1303 regulates BBB permeability and promotes CNS lesions following CA16 infections by directly targeting MMP9.
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miR-1303通过直接靶向MMP9调节BBB通透性并促进CA16感染后CNS损伤
DOI：
10.1038/s41426-018-0157-3
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发表时间：
2018-09-19
影响因子：
13.2
通讯作者：
Liu L
中科院分区：
文献类型：
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作者：
Song J;Hu Y;Li H;Huang X;Zheng H;Hu Y;Wang J;Jiang X;Li J;Yang Z;Fan H;Guo L;Shi H;He Z;Yang F;Wang X;Dong S;Li Q;Liu L
柯萨奇病毒A16（CA 16）是小核糖核酸病毒科的一员，可引起婴儿和幼儿的轻度和自限性手足口病（HFMD）。CA 16感染也可进展为中枢神经系统（CNS）并发症;然而，CA 16穿透血脑屏障（BBB）并随后引起CNS损伤的潜在机制仍不清楚。本研究旨在通过建立CA 16感染的体外血脑屏障模型和CA 16感染的恒河猴幼猴体内模型，探讨CA 16嗜神经性的机制。结果表明，CA 16感染引起血脑屏障通透性增加，并伴有基质金属蛋白酶9（MMP 9）表达上调。随后，高通量miRNA测序技术和生物信息学分析显示，miR-1303可能通过靶向MMP 9调节血脑屏障通透性。接下来，我们使用双荧光素酶、qRT-PCR和蛋白质印迹分析来提供miR-1303靶向MMP 9的证据。进一步的实验表明，CA 16感染促进了连接复合物（Claudin 4，Claudin 5，VE-钙粘蛋白和ZO-1）的降解，可能是通过下调miR-1303和上调MMP 9。最后，EGFP-CA 16感染可以通过促进连接复合物的降解进入CNS，最终引起神经炎症和CNS损伤，这使用体内恒河猴模型证实。我们的研究结果表明，CA 16可能穿透血脑屏障，然后通过下调miR-1303进入CNS，miR-1303通过直接调节MMP 9破坏连接复合物，最终导致CNS病理变化。这些结果为CA 16感染后的手足口病患者提供了新的治疗靶点。
Coxsackievirus A16 (CA16) is a member of the Picornaviridae family and causes mild and self-limiting hand, foot, and mouth disease (HFMD) in infants and young children. CA16 infection can also progress to central nervous system (CNS) complications; however, the underlying mechanism by which CA16 penetrates the blood-brain barrier (BBB) and then causes CNS damage remains unclear. This study aimed to explore the mechanism of CA16 neurotropic tropism by establishing an in vitro BBB model with CA16 infection and an in vivo CA16 rhesus monkey infant infection model. The results showed that CA16 infection induced increased permeability of the BBB accompanied by upregulation of matrix metalloproteinase 9 (MMP9) expression. Subsequently, high-throughput miRNA sequencing technology and bioinformatics analysis revealed that miR-1303 may regulate BBB permeability by targeting MMP9. Next, we used dual-luciferase, qRT-PCR, and western blot assays to provide evidence of MMP9 targeting by miR-1303. Further experiments revealed that CA16 infection promoted the degradation of junctional complexes (Claudin4, Claudin5, VE-Cadherin, and ZO-1), likely by downregulating miR-1303 and upregulating MMP9. Finally, EGFP-CA16 infection could enter the CNS by facilitating the degradation of junctional complexes, eventually causing neuroinflammation and injury to the CNS, which was confirmed using the in vivo rhesus monkey model. Our results indicate that CA16 might penetrate the BBB and then enter the CNS by downregulating miR-1303, which disrupts junctional complexes by directly regulating MMP9 and ultimately causing pathological CNS changes. These results provide new therapeutic targets in HFMD patients following CA16 infection.
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